3beta-hydroxy-5, 6-dihalo-16alpha, 17alpha-epoxy-21-bromopregnan-20-ones and derivatis thereof



Unitlid 11 8 tent 35-HYDROXY-5,'6-DIHALO'- 1'6a,17a-EPOXY-2l-BRO-MOPREGNAN 20 0NES-AND DERIVATIVES THEREOF I Bjarte Loken, Sarpsborg,--Norway No Drawing. Application February 9,1959

"Serial No.791,8 41 '5 Claims. (Cl. 260 -239555) The presentinventionfrelates t'o a novel method im the preparation of17a,2l-dihydroxyprogesterone and to to'a mixture "of the '6a-halo and65-hal'o derivatives of 2l-acyloxy-16a,17wepoxy-4-pregnerie 3,20 dione"(if the structural formula cmoc'ouowemikyl) wherein X is halogen, byheating with an alkali metal alkanoate derived from such lower alkanoicacids as acetic, propionic, butyric, pentanoic, or hexanoic acids. Thereaction can be carried out in an inert organic solvent such as a loweralkanone, e.g. acetone, butanone, or pentanone. This epoxide is thentreated with anhydrous hydrogen halide in a lower alkanoic acid solventto yield a 6,165-dihalo-17a-hydroxy-21-acyl0xy-4-pregnene-3,20-dionewherein there is an admixture of the 6m and 65-halo derivatives. Thelatter is triturated in a lower alkanoic acid solvent in the presence ofa suitable catalyst, preferably Raney nickel. In this manner there areobtained the 17 a-hydroXy-Zl-acycloxyprogesterones, which are known anduseful intermediates for the preparation of adrenocorticoid hormones.

The invention will appear more fully from the following examples whichare given only for purposes of illustration and are not to be construedas limiting the invention in spirit or in scope. Quantities areindicated as parts by weight.

Example 1 A solution of 2.8 parts of sodium hydroxide in aqueousmethanol is added portionwise to a solution of 45 parts of 35,170:dihydroxy 5u,65,165,21 tetrabromopregnan-ZO-one in 200 parts ofmethanol. Water is added to the solution and the35-hydroxy-5a,65,2l-tribromol6a,17u-epoxypregnan-20-one, whichprecipitates, is recovered by filtration. Upon recrystallization fromethanol, the product 'melts at about 124- 126 C. and'has the specificoptical rotation of 28 in chloroform.

A solution of 4 parts of chromium trioxidein a'rnixture of 10 parts ofWater and 25 parts of acetic acid is added portionwise to a solution of15.pa'rts of 35- hydroxy 5 a,65,21 tribromo 16a,17a epoxypregiian-20-one in a mixture 015300 parts of acetic acid and 134 parts ofdichloromethane. During this addition the temperature is maintainedbelow 10 C. The mixture is then allowed to reach room temperatureand'water is added to precipitate the product which is collected on'afilter and recrystallized from a mixture of 'dichloromethane andmethanol to .yield 5a,65,21-tribromo l'6u, 17u-epoxypregnane-3,20-dionedecomposing at about 114 C., and having'the specific optical rotatidn of"-'3 1 in chloroform. This product'is an admixture with the55,6a,21-tribromo isomer.

Example 2 A solution of 7.5 parts of-5'a,65,'2l-tribromo-16a,17aepoxypregnane-3, 20-dione in parts ofacetone is refluxed in the presence of 12.5 'parts of anhydrous potassumacetate for 3 hours. Water is added-and the oily precipitate isextracted with dichloromethane. The extract" is washed withwater, driedover anhydrous PO? tassium carbonate, 'filtered, and evaporated to :give6- bromo 1'6a,17a epoxy 21 acetoxy 4 pregnene- 3,20'-dione which has thespecific optical rotation of +'42 in chloroform. The compound isobtained'as =anoil.

Substitution of 16.1 parts of potassium butyrate for the potassiumacetate in the preceding procedure yields the oily6-bromo-16a,17u-epoxy-21-butyroxy-4 pregnene- 3,20-dione.

Example 3 For about 15 minutes 5 parts of 6-b1'0m0-16a,17o:- epoxy 21acetoxy 4 pregnene 3,20 dione is stirred in a 1:5 mixture of hydrogenbromide in acetic acid. The solution is then poured into an excess ofwater and the precipitate thus obtained is recovered by filtration. The6,165 dibromo 17oz hydroxy 21 acetoxy 4- pregnene-3,20-dione has thespecific optical rotation of +24 in chloroform.

Substitution of 6.5 parts of 6-br0mo-16a,17a-epoxy-21butyroxy-4-pregnene-3,20-dione for the 6-bromo-16u,-17a-epoxy-21acetoxy-4-pregnene-3,20-dione in the preceding procedureyields 6,165-dibromo-17a-hydroxy-2lbutyroxy-4-pregnene-3,20-dione.

Example 4 The 6,165 dibromo 17a hydroxy 21 acetoxy-4-pregnene-3,20-dione obtained in the preceding example is dissolved inmethanol and the solution is stirred for about 24 hours in the presenceof Raney nickel. The reaction mixture is filtered and the filtrate isconcentrated to a small volume to induce crystallization. Theprecipitate is collected on a filter and recrystallized from acetone toyield 17u-hydroxy-21-acetoxy-4-pregnene-3,20- dione melting at about235-238 C. The specific optical rotation is about +133 in chloroform.

Substitution of an equimolar amount of 6,165-dibromo- 17a hydroxy 21butyroxy 4 pregnene 3,20 dione for the6,165-dibromo-17a-hydroxy-2l-acetoxy-4-pregnene-3,20-dione in thepreceding paragraph yields white, crystalline a hydroxy 21 butyroxy 4pregnene- 3,20-dione.

Example 5 To a mixture of 15 parts of 35,l7a-dihydroxy-5m,65-dichlorod65,21-dibromopregnan-20-one in 67 parts of methanol is addedportionwise a solution of 1 part of sodium hydroxide in-aqueousmethanol. Upon the addition of water, there precipitates the35-hydroxy-5a,65-

dichloro 160:,176: epoxy 21 bromopregnan 20- one which is collected on afilter and recrystallized from Z-propanol.

, While the temperature is maintained below 5? C., a solution of 1.3'parts of chromium trioxide in a mixture' of 3.3 parts of water and 8parts of acetic acid is added portionwise to a cold solution of 5 partsof 3,8 hydroxy 50:,613 dichloro 1 6a,17 x epoxy 21- bromopregnan-ZO-onein a mixture of 100 parts of acetic acid and 35 pa'rts of chloroform.The solution is then warmed to room temperature. Water is added,whereupon there precipitate the white, prismatic crystals of '50:,65dichloro 1611,17 epoxy 21 bromopregnane-'3,20-dione.which are recoveredby filtration and recrystallized from a mixture of ethanol andchlorofrm. a

. Example 6 A mixture of 4 parts of anhydroustsodium acetate and 2.5parts of 5u,6;3 dichloro 1611,17 epoxy 21- bromopregnane-3,20-dione in40 parts of benzene is refiuxed for four hours. The water is added andthe resulting precipitate is extracted with chloroform, washed withwater, dried over anhydrous sodium sulfate, 111- 1 tered, and evaporatedto yield 6 chloro 1601:,1702- epoxy 21 acetoxy 4 pregnene 3,20 dione.

A solution of 1.2 parts of 6 chloro-160c,17uepoxy-21-acetoxy-4-pregnene-3,20-dione in a 20% hydrogenbromide solution in acetic acid is poured into an excess of water. Theprecipitate thus obtained is collected on a filter to yield6-611101'0-1613-131'01110-17oz-hydroxy-21-acetoxy-4-pregnene-3,20-dione.Dehalogenation with Raney nickel by the procedure of Example 4 yields17oz hydroxy 21 acetoxy 4 pregnene' 3,20-

dione melting at about 236-239 C. What is claimed is:

1. 5u,6,B,21 tribromo 16a,17u epoxypregnane-3,20- dione. i a

2. A compound a: the structural formula wherein R is a radical of thestructural formula C() (lower alkyl) and X is a radical of the classconsisting of chlorine and bromine.

5. 6,165 dibromo 17a hydroxy 21 acetoxy- 4-pregnene-3,20-dione.

References Cited the file of this patent UNITED STATES PATENTS 2,602,769Murray et a1. July 8, 1952 2,789,989 Julian et al. Apr. 23, 19572,811,522 Cutler Oct. 29, 1957 2,816,108 Julian et a1. Dec. 10, 19572,874,154 Stork et al. Feb. 17, 1959

1. SA.6B,21-TRIBROMO-16A,17A-EPOXYPREGNANE-3,20DIONE.
 2. A COMPOUND OF ASTRUCTURAL FORMULA